Engineering biomimetic silk fibroin hydrogel scaffolds with “organic-inorganic assembly” strategy for rapid bone regeneration

Although natural polymers have been widely used in constructing bone scaffolds, it still remains challenging to fabricate natural polymer-derived bone scaffolds with biomimetic mechanical properties as well as outstanding osteogenic properties for large-size and weight-bearing bone defects regeneration. Herein, an “organic-inorganic assembly” strategy is developed to construct silk fibroin (SF)-based bone scaffolds with the aforementioned merits. After secondary structure reshuffling, the 3.3-fold increment of β-sheet structures in SF hydrogel resulted in a 100-fold improvement of mineral-assembly efficacy via influencing the ion adsorption process and providing templates for mineral growth. Notably, abundant minerals were deposited within the hydrogel and also on the surface, which indicated entire mineral-assembly, which ensured the biomimetic mechanical properties of the digital light processing 3D printed SF hydrogel scaffolds with haversian-mimicking structure. In vitro experiments proved that the assembly between the mineral and SF results in rapid adhesion and enhanced osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. In vivo experiments further proved that the mineral-assembled SF hydrogel scaffold could significantly enhance integration and bone regeneration at the weight-bearing site within one month. This SF-based “organic-inorganic assembly” strategy sheds light on constructing cell-free, growth factor-free and natural polymer-derived bone scaffolds with biomimetic 3D structure, mechanical properties and excellent osteogenic properties. • Inspired by the assembly and structure of natural bone matrix, we engineered a biomimetic bone graft using silk fibroin (SF) hydrogel and a molecular-modulation strategy (“organic-inorganic assembly” strategy) as well as DLP 3D printing. • In this study, the regulation of silk fibroin molecular secondary structure efficiently enhanced SF hydrogel mineralization both in vitro and in vivo. The β-sheet crystallites promote the formation of mineral granules both on the surface and within the SF hydrogel. • Notably, a 3.3-fold increment of β-sheet crystallites led to a remarkable 100-fold increase of the mineral granules, assembled inside the SF hydrogel. • The assembly between the mineral and the SF hydrogel significantly enhanced the mechanical and osteogenic properties of the SF hydrogel scaffolds, constructed with DLP 3D printing. • Our strategy is a cell-free, ready-to-use, and revolutionary therapeutics for bone regeneration; it also illustrated a bottom-up approach to combine material science and bionics for the design of targeted tissue scaffolds.